Felodipine, Formula 1, is a 1,4 dihydropyridine derivative for use as an antihypertensive and muscle relaxant drug. Other phenyl-1,4 dihydropyridine compounds have been disclosed which have therapeutic activity in the treatment of heart disease, see U.S. Pat. No. 5,310,917. ##STR1##
The preparation of felodipine and related compounds typically involves a multistep synthesis, the last step of which usually involves formation of the dihydropyridine ring. U.S. Pat. No. 5,310,917 describes a synthesis involving heating a mixture of a benzylidine with an amino crotonate ester in the presence of a strong acid to yield the desired dihydropyridine product U.S. Pat. No. 4,600,778 describes a process for the preparation of dihydropyridine compounds by reacting a ketocarboxylic ester with an aldehyde, and a catalytic amount of piperidine acetate in an aliphatic alcohol as solvent. Both patents are herein incorporated by reference in their entirety.
Disadvantages with most of the disclosed syntheses for the preparation of dihydropyridine derivatives, and in particular felodipine, include (1) an extractive workup to isolate the desired product; (2) the formation of symmetrical ester byproducts which are difficult to isolate from the desired final compound; (3) use of acids in the reaction which require a neutralization step(s) to remove. The extractive workup and removal of byproducts are labor intensive procedures. From a commercial viewpoint, the use of acids is often costly and environmentally unfriendly. It is preferred to avoid their use and any potential dangers associated with the use of acids.
There is thus a continuing need for a commercially viable, synthetic route for the production of dihydropyridine compounds and, in particular felodipine.